Intracellular receptors (IRs) form a class of structurally-related genetic regulators scientists has named “ligand dependent transcription factors” (R. M. Evans, Science, 240:889, 1988). Steroid receptors are a recognized subset of the IRs, including androgen receptor, progesterone receptor (PR), estrogen receptor (ER), glucocorticoid receptor (GR), and mineralcorticoid receptor (MR). Regulation of a gene by such factors requires both the IR itself and a corresponding ligand, which has the ability to selectively bind to the IR in a way that affects gene transcription.
The natural hormones for steroid receptors have been known for a long time, such as testosterone for the androgen receptor. A synthetic compound that binds to an IR and mimics the effect of the native hormone is referred to as an “agonist”, while a compound that inhibits the effect of the native hormone is called an “antagonist”. The term “modulators” refers to a group of compounds that have a spectrum of activities from agonist, partial agonist to antagonist in different target tissues.
Androgen receptor modulators are known to play an important role in health of both men and women. For example, androgen receptor antagonists, such as cyproterone acetate, flutamide and casodex, are useful in the treatment of prostatic hyperplasia and cancer of the prostate. Androgen receptor agonists, such as testosterone and fluoxymesterone, are used in the treatment of hypogonadism and muscle wasting diseases. Due to increased life expectancies, development of tissue selective, safer, orally active androgen receptor modulators are desirable to improve quality of life.
A group of 6-cycloamino-quinolinone derivatives was recently described as androgen receptor modulators (e.g., U.S. Pat. No. 6,566,372). This group of androgen receptor modulators was developed by using cell-based high-throughput assays, termed cotransfection assays.